His mother was Austrian; his father was Hungarian. He did much important theoretical work on the non-specific response of the organism to stress. While he did not recognize all of the many aspects of glucocorticoids, Selye was aware of their role in this response. Some commentators considered him the first to demonstrate the existence of a separate stress disease, the stress syndrome, or general adaptation syndrome (GAS).

His initial inspiration for GAS came from an endocrinological experiment in which he injected mice with extracts of various organs. He at first believed to have discovered a new hormone but was proved wrong when every irritating substance he injected produced the same symptoms (swelling of the thymus, atrophy of the adrenal cortex, gastric and duodenal ulcers). This, paired with his observation that people with different diseases exhibit similar symptoms, led to his description of the effects of "noxious agents" as he at first called it. He later coined the term "stress", which has been accepted into the lexicon of various other languages.

To grossly oversimplify to the point of circular argument, Selye discovered and documented that stress differs from other physical responses in that stress is stressful whether the one receives good or bad news, whether the impulse is positive or negative. He called negative stress distress and positive stress eustress. The system whereby the body copes with stress, the hypothalamus-pituitary-adrenal axis]], was also first described by Selye.

He wrote Stress without Distress (1974), The Stress of Life (1956), and From dream to discovery; on being a scientist (1964). He worked as a professor and director of the Institute of Experimental Medicine and Surgery at the Université de Montréal.